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Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles.
Free Radic Biol Med. 2019 01; 130:408-418.FR

Abstract

Chagas disease is caused by the hemoflagellate protozoa Trypanosoma cruzi and is one of the most important neglected tropical diseases, especially in Latin American countries, where there is an association between low-income populations and mortality. The nitroderivatives used in current chemotherapy are far from ideal and present severe limitations, justifying the continuous search for alternative drugs. Since the1990s, our group has been investigating the trypanocidal activity of natural naphthoquinones and their derivatives, and three naphthoimidazoles (N1, N2 and N3) derived from β-lapachone were found to be most effective in vitro. Analysis of their mechanism of action via cellular, molecular and proteomic approaches indicates that the parasite mitochondrion contains one of the primary targets of these compounds, trypanothione synthetase (involved in trypanothione production), which is overexpressed after treatment with these compounds. Here, we further evaluated the participation of the mitochondria and reactive oxygen species (ROS) in the anti-T. cruzi action of naphthoimidazoles. Preincubation of epimastigotes and trypomastigotes with antioxidants (α-tocopherol and urate) strongly protected the parasites from the trypanocidal effect of naphthoimidazoles, decreasing the ROS levels produced and reverting the mitochondrial swelling phenotype. The addition of pro-oxidants (menadione and H2O2) before the treatment induced an increase in parasite lysis. Despite the O2 uptake and mitochondrial complex activity being strongly reduced by N1, N2 and N3, urate partially restored the mitochondrial metabolism only in N1-treated parasites. In parallel, MitoTEMPO, a mitochondrial-targeted antioxidant, protected the functionality of the mitochondria in N2- and N3-treated parasites. In addition, the trypanothione reductase activity was remarkably increased after treatment with N1 and N3, and molecular docking demonstrated that these two compounds were positioned in pockets of this enzyme. Based on our findings, the direct impairment of the mitochondrial electron transport chain by N2 and N3 led to an oxidative misbalance, which exacerbated ROS generation and led to parasite death. Although other mechanisms cannot be discounted, mainly in N1-treated parasites, further investigations are required.

Authors+Show Affiliations

Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.Laboratório de Pesquisa Clínica em Dermatozoonoses em Animais Domésticos, Instituto Nacional de Infectologia, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.Instituto de Ciências Exatas, Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Maceió, Brazil.Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Maceió, Brazil.Instituto de Ciências Exatas, Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. Electronic address: rubemsadok@gmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30445126

Citation

Bombaça, Ana Cristina S., et al. "Mitochondrial Disfunction and ROS Production Are Essential for anti-Trypanosoma Cruzi Activity of Β-lapachone-derived Naphthoimidazoles." Free Radical Biology & Medicine, vol. 130, 2019, pp. 408-418.
Bombaça ACS, Viana PG, Santos ACC, et al. Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles. Free Radic Biol Med. 2019;130:408-418.
Bombaça, A. C. S., Viana, P. G., Santos, A. C. C., Silva, T. L., Rodrigues, A. B. M., Guimarães, A. C. R., Goulart, M. O. F., da Silva Júnior, E. N., & Menna-Barreto, R. F. S. (2019). Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles. Free Radical Biology & Medicine, 130, 408-418. https://doi.org/10.1016/j.freeradbiomed.2018.11.012
Bombaça ACS, et al. Mitochondrial Disfunction and ROS Production Are Essential for anti-Trypanosoma Cruzi Activity of Β-lapachone-derived Naphthoimidazoles. Free Radic Biol Med. 2019;130:408-418. PubMed PMID: 30445126.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles. AU - Bombaça,Ana Cristina S, AU - Viana,Paula G, AU - Santos,Augusto C C, AU - Silva,Thaissa L, AU - Rodrigues,Aline Beatriz M, AU - Guimarães,Ana Carolina R, AU - Goulart,Marilia O F, AU - da Silva Júnior,Eufrânio N, AU - Menna-Barreto,Rubem F S, Y1 - 2018/11/14/ PY - 2018/07/25/received PY - 2018/11/02/revised PY - 2018/11/12/accepted PY - 2018/11/18/pubmed PY - 2018/11/18/medline PY - 2018/11/17/entrez KW - Antioxidant defenses KW - Chagas disease KW - Chemotherapy KW - Mitochondria KW - Naphthoimidazoles KW - Reactive oxygen species KW - Trypanosoma cruzi SP - 408 EP - 418 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 130 N2 - Chagas disease is caused by the hemoflagellate protozoa Trypanosoma cruzi and is one of the most important neglected tropical diseases, especially in Latin American countries, where there is an association between low-income populations and mortality. The nitroderivatives used in current chemotherapy are far from ideal and present severe limitations, justifying the continuous search for alternative drugs. Since the1990s, our group has been investigating the trypanocidal activity of natural naphthoquinones and their derivatives, and three naphthoimidazoles (N1, N2 and N3) derived from β-lapachone were found to be most effective in vitro. Analysis of their mechanism of action via cellular, molecular and proteomic approaches indicates that the parasite mitochondrion contains one of the primary targets of these compounds, trypanothione synthetase (involved in trypanothione production), which is overexpressed after treatment with these compounds. Here, we further evaluated the participation of the mitochondria and reactive oxygen species (ROS) in the anti-T. cruzi action of naphthoimidazoles. Preincubation of epimastigotes and trypomastigotes with antioxidants (α-tocopherol and urate) strongly protected the parasites from the trypanocidal effect of naphthoimidazoles, decreasing the ROS levels produced and reverting the mitochondrial swelling phenotype. The addition of pro-oxidants (menadione and H2O2) before the treatment induced an increase in parasite lysis. Despite the O2 uptake and mitochondrial complex activity being strongly reduced by N1, N2 and N3, urate partially restored the mitochondrial metabolism only in N1-treated parasites. In parallel, MitoTEMPO, a mitochondrial-targeted antioxidant, protected the functionality of the mitochondria in N2- and N3-treated parasites. In addition, the trypanothione reductase activity was remarkably increased after treatment with N1 and N3, and molecular docking demonstrated that these two compounds were positioned in pockets of this enzyme. Based on our findings, the direct impairment of the mitochondrial electron transport chain by N2 and N3 led to an oxidative misbalance, which exacerbated ROS generation and led to parasite death. Although other mechanisms cannot be discounted, mainly in N1-treated parasites, further investigations are required. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/30445126/Mitochondrial_disfunction_and_ROS_production_are_essential_for_anti_Trypanosoma_cruzi_activity_of_β_lapachone_derived_naphthoimidazoles_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(18)31288-7 DB - PRIME DP - Unbound Medicine ER -